Method for reducing development of free radical induced malignancies

ABSTRACT

This invention relates to a method of treating patients at risk of developing a free radical induced malignancy. The method includes administering an effective amount of a thiol or reducible disulfide compound according to the formula set forth in the specification to a patient at risk.

FIELD OF THE INVENTION

This invention relates to a method for reducing or preventing theformation of free radical induced malignancies in patients at risk. Themethod involves administering an effective amount of a disulfide orthiol-containing compound to a patient at risk of developing freeradical induced malignancies.

BACKGROUND OF THE INVENTION

Many malignant tumors are thought to arise due to cellular injury andDNA mutations and deletions mediated by the action of free radicals.Free radicals are highly reactive and damaging to cells, particularly togenomic DNA. Alteration of the cellular make-up often causes mutationsin the genetic material, and, as the mutated cells continue to divideand/or live longer than their normal counterparts, is thought to be oneof the causes of malignancy formation.

Free radicals are normally present in the body in minute amounts.Exposure to high energy sources, such as X-rays, ultraviolet or infraredlight, or forms of ionizing radiation can stimulate the production offree radicals in high quantities. Free radicals are also formed innormal biochemical redox reactions and may also be formed by ingestedtoxins.

Natural enzymes present in the body generally are sufficient toeliminate most free radicals, but propagation of free radicals canoverrun these enzymes and cause significant cellular damage. The variousskin cancers are the most common form of free radical inducedmalignancies.

Mesna (sodium 2-mercaptoethene sulfonate) and dimesna (disodium2,2'-dithiobis ethane sulfonate) are known therapeutic compounds whichhave heretofore demonstrated a wide variety of therapeutic uses. Bothmesna and dimesna have been shown to be effective protective agentsagainst certain specific types of toxicity associated with theadministration of cytotoxic drugs used to treat patients for varioustypes of cancer.

In particular, mesna has been used with some success in mitigating thetoxic effects of cytotoxic agents such as ifosfamide, oxazaphosphorine,melphalane, cyclophosphamide, trofosfamide, sulfosfamide, chlorambucil,busulfan, triethylene thiophosphamide, triaziquone, and others, asdisclosed in U.S. Pat. No. 4,220,660, issued Sep. 2, 1980.

The near absence of toxicity of dimesna further underscores theusefulness of this compound, as large doses that may be needed can begiven to a patient without increasing the risk of adverse effects fromthe protective agent itself.

Further, pharmacological profiles of each compound indicate that, ifproper conditions are maintained, mesna and dimesna do not prematurelyinactivate primary therapeutic drugs to a significant degree. Thus,neither compound will significantly reduce activity of thechemotherapeutic agent, and in many cases, act to potentiate the effectof the main drug on targeted cancer cells.

The structures of both mesna and dimesna are shown below as Formula Aand Formula B respectively. ##STR1##

As is well known, dimesna is a dimer of mesna, with the optimumconditions for oxidation occurring in the slightly basic (pH˜7.3),oxygen rich environment found in blood plasma. In mildly acidic, lowoxygen conditions, in the presence of a reducing agent such asglutathione reductase, conditions prevalent in the kidneys, the primaryconstituent is mesna.

Mesna acts as a protective agent for a number of cytotoxic agents bysubstituting a nontoxic sulfhydryl moiety for a toxic hydroxy (or aquo)moiety. This action is particularly evidenced in the coadministration ofmesna and oxazaphosphorine, and in the administration of dimesna alongwith cisplatin or carboplatin.

Mesna and dimesna, as well as some analogues of these compounds, haveexcellent toxicity profiles in mammalian species. In fact, dimesna hasbeen administered intravenously to mice and dogs in doses higher thanthe accepted oral LD₅₀ for common table salt (3750 mg/kg), with noadverse effects. Dimesna has also been administered to humans in dosesexceeding 15 g/m², with no adverse effects.

Mesna, and other analogues with free thiol moieties, constitute the morephysiologically active form of the two types of compounds described inthis specification. These compounds manifest their activity by providingfree thiol moieties for terminal substitution at locations where aterminal leaving group of appropriate configuration is located.

Dimesna and other disulfides can be activated intracellularly byglutathione reductase, a ubiquitous enzyme, thereby generating highconcentrations of intracellular free thiols. These free thiols act toscavenge the free radicals and other nucleophilic compounds oftenresponsible for causing cell damage.

This profile is especially significant in explaining the success ofdimesna in controlling and mitigating the toxic effects of platinumcomplex antitumor drugs. The mechanism for action in the case ofcisplatin (cis-diammine dichloro platinum) is explained in U.S. Pat. No.5,789,000, which is incorporated herein by reference.

Mesna, dimesna, and analogues of these compounds have been the subjectof several prior pharmaceutical uses described in the literature and inprior patents, both in the United States and around the world. Inaddition to the cytotoxic agent protection uses, one or more of thesecompounds have proven effective, in vitro, against a multiplicity ofbiological targets, and have been effective, in vivo, in the treatmentof sickle cell disease, radiation exposure, chemical agent exposure, andother uses.

Mesna, dimesna, and analogues thereof are synthesized from commonlyavailable starting materials, using acceptable routes well-known in theart. One such method involves the two-step, single pot synthetic processfor making dimesna and like compounds of the following formula:

    R.sub.1 --S--R.sub.2 ;

wherein:

R₁ is hydrogen, X-lower alkyl, or X-lower alkyl-R₃ ;

R₂ is -lower alkyl-R₄ ;

R₃ and R₄ are each individually SO₃ M or PO₃ M₂ ;

X is absent or X is sulfur; and

M is an alkali metal.

The process essentially involves a two step single pot synthetic processwhich results in the conversion of an alkenyl sulfonate salt or acid tothe desired formula I compound. The process in the case of mesna is asingle step process which converts the alkenyl sulfonate salt to mesnaor a mesna derivative by reacting with an alkali metal sulfide or withhydrogen sulfide.

If the desired end product is dimesna or a dimesna analogue, a two-stepsingle pot process is involved. Step 1 is as described above. Step 2 ofthe process is performed in the same reaction vessel as Step 1 withoutthe need to purify or isolate the mesna formed during that step. Step 2includes the introduction of oxygen gas into the vessel, along with anincrease in pressure and temperature above ambient values, at least 20pounds per square inch (psi) and at least 60° C. Dimesna or a derivativethereof is formed in essentially quantitative yield.

Other processes, well-known and documented in the prior art, may beemployed to make either mesna or dimesna, or derivatives and analoguesthereof.

SUMMARY OF THE INVENTION

This invention involves the administration of an effective amount ofcompounds of formula I, below, for treating patients suffering from freeradical induced malignancies. ##STR2## wherein: R₁ is hydrogen, loweralkyl or ##STR3## R₂ and R₄ are each individually SO₃ ⁻ M⁺, PO₃ ²⁻ M₂²⁺, or PO₂ S²⁻ M₂ ²⁺ ;

R₃ and R₅ are each individually hydrogen, hydroxy or sulfhydryl;

m and n are individually 0, 1, 2, 3 or 4, with the proviso that if m orn is 0, then R₃ is hydrogen; and

M is hydrogen or an alkali metal ion; or

a pharmaceutically acceptable salt thereof.

Effective amounts of the formula I compounds to be administeredaccording to the method of this invention vary, and depend on theseverity of the patient's risk of developing a malignancy.

Accordingly, it is an object of this invention to provide for a methodof safely and effectively reducing the occurrence of or preventing freeradical induced malignancies.

Other objects will become apparent upon a reading of the followingdescription.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The preferred embodiments herein described are not intended to beexhaustive nor to limit the invention to the precise form disclosed.They are chosen and described to explain the principles of theinvention, and its application and practical use to best enable othersskilled in the art to follow its teachings.

The method of this invention involves the administration of an effectiveamount of a formula I compound to a patient at risk of developing a freeradical induced malignancy. Administration may be either oral orparenteral.

The effective amount of the formula I compound will necessarily dependupon the severity of the risk of the patient's developing a free radicalinduced malignancy. Since the formula I compounds are essentiallynontoxic, large amounts can be safely administered.

The preferred dosage to reduce the risk free radical inducedmalignancies may be as low as 0.1 mg/kg up to 1,000 mg/kg. The moresevere the risk, the more formula I compound should be administered toprovide an effective response. The patient at risk must replenish theplasma supply of formula I compound frequently to obtain maximumbenefits of the agent.

Administration is preferably through parenteral or oral routes, mostpreferably oral. For parenteral administration, the formula I compoundis dissolved in a suitable solvent, most preferably water, to produce asolution which may be injected or infused. One or more pharmaceuticallyacceptable excipients may also be added to provide for an elegantformulation.

For oral administration the formula I compound is preferably combinedwith one or more pharmaceutically acceptable excipients, fillers and/ordiluents. Oral dosage forms may include pills, caplets, tablets, andothers. Alternatively, the formula I compound may be contained in aswallowable container such as a gelatin capsule or the like.

Administration of the formula I compound should be prescribed as soon aspossible after determining the patient's risk of generating a freeradical induced malignancy. Preferred initial dose is between 20 mg/kgand 500 mg/kg per day, usually in split or multiple doses. Persons withthe highest risk of developing a free radical induced malignancy arethose who spend large amounts of time exposed to the rays of the sun.

Other accepted methods may also be combined with the Administration ofthe formula I compound. Due to the excellent safety profile and therapid clearance rate, additional doses of the formula I compound may beadministered safely.

It is understood that the above description is in no way limiting of theinvention, which may be modified within the scope of the followingclaims.

What is claimed:
 1. A method of reducing the risk of a patientdeveloping a free radical induced malignancy, said method comprisingadministering an effective amount of a compound of formula I: ##STR4##wherein: R₁ is lower alkyl or ##STR5## R₂ and R₄ are each individuallySO₃ ⁻ M⁺, PO₃ ²⁻ M₂ ²⁺, or PO₂ S²⁻ M₂ ²⁺ ;R₃ and R₅ are eachindividually hydrogen, hydroxy or sulfhydryl; m and n are individually0, 1, 2, 3 or 4, with the proviso that if m or n is 0, then R₃ ishydrogen; and M is hydrogen or an alkali metal ion; ora pharmaceuticallyacceptable salt thereof.
 2. The method of claim 1 wherein the effectiveamount of the formula I compound administered is from 0.1 mg/kg of bodyweight to 1,000 mg/kg of body weight.
 3. The method of claim 1 whereinthe compound is administered orally.
 4. The method of claim 1 whereinthe compound is administered parenterally.